Hi everybody, thank you for joining us today. I'm here to introduce Vicore Pharma. Today with us we have the CEO, Ahmed Mousa. I'm an analyst in the TD Cowen and Healthcare Investment Banking Group, and I'll be around if you have any questions afterwards, but, yeah, I'm happy to hand it over to you.
Perfect, thank you Emily. Hi everyone, thanks for joining. Yeah, I'm Ahmed Mousa, relatively new CEO of Vicore, been in the role for about five months now and really excited to tell you more about what we're working on. For background, Vicore Pharma is a company that's really been focused in the angiotensin II pathway and understanding and modulating this angiotensin II type 2 receptor that I'm excited to tell you more about, which we believe is a really nice upstream target that can play a role in a number of diseases, starting with idiopathic pulmonary fibrosis. Company footprint is in Stockholm and Copenhagen, and then I'm based here, in the Boston area as well. We're publicly listed on the NASDAQ in Stockholm with about $150 million market cap, and fortunate to be supported by some nice specialists out of Europe.
HealthCap and HBM have been longstanding shareholders, and then more recently bringing on U.S. names into the company: OrbiMed, Suvretta, as well as Invus. In terms of the company's pipeline, you know, the true kind of focus for us is the development of C21 and IPF, where we've shown some nice interim data and are planning to do final data disclosure in the first half of this year. We're also planning to initiate a phase IIB, a global phase IIB study in the first half of this year in IPF as well. And we recently also announced a partnership for the drug in Japan, which I'm happy to talk more about. We're also thinking about other indications and other molecules beyond C21 and IPF and are continuing to do that work.
And in addition we have a nice digital therapy that has impact for patients who are suffering from anxiety associated with pulmonary fibrosis, as well. But really going to then the focus, right, idiopathic pulmonary fibrosis, you know, why are we excited about this disease as a potential area to develop new therapies? There's such a high unmet need. You know, IPF is a disease that has unfortunately a pretty tough prognosis, three to five year survival. And the two standard of care therapies that are available, you know, account for that, you know. And unfortunately, in addition to having limited therapeutic efficacy, the standard of care therapies also have quite tough side effects, gastrointestinal side effects.
Actually because of that, only about 26% of patients in the United States initiate treatment of these therapies in the first place, and also there's a high discontinuation rate of about 10 months. Now, notwithstanding everything I just said, it still is something that's a $4.3 billion global market that continues to increase every year, and so it's also a very interesting, you know, commercial opportunity as well. I think the bigger challenge, of course, than in IPF is that there have been a number of failures, both recently and over the past years in, in, in seeking to treat this disease. And so the question becomes, why is agonizing this angiotensin II type 2 receptor an interesting way to go after this disease, and how is it maybe different from some of the other approaches that have been attempted?
You know, so this is a schematic of the angiotensin II pathway at the left here, and the primary targets that angiotensin II peptide activates are the AT1R and the AT2R. These receptors do essentially the opposite of each other. So the AT1R is a hypertensive, inflammatory, and fibrotic pathway. And if you think about the development of ACE inhibitors and angiotensin receptor blockers, they're essentially built to stop that pathway from being activated because of the hypertension and effects on blood pressure. What's interesting is this AT1 receptor is quite broadly expressed in healthy humans, so it's broadly expressed in tissues, and it's kind of pretty constitutively expressed as well. In contrast, this AT2 receptor that we're going after in a selective way is quite limited expression, both in tissue and in time.
So actually in most tissues you don't find the AT2 receptor expressed in a basal state. Instead it tends to be upregulated in a disease state. But actually one of the very few tissues where you'll find the AT2 receptor expressed basally is the lung, and we think that's because folks are always breathing in a little bit of pollution, virus, bacteria, and so there's always a little bit of immune fibrotic response, inflammatory response, that needs to be resolved. And that's exactly what this mechanism does. It's anti-fibrotic, it's vasodilatory, it's anti-inflammatory, and it drives a number of those mechanisms, and that's one of the reasons why we're so excited about it. It sits quite nicely, you know, kind of upstream.
And so while others have gone after maybe downstream antagonism to go after IPF, like blocking something in the fibrotic cascade, we think that this is a quite nice way to go after such a, you know, kind of profound pathology. In addition to kind of having that type of effect, we think that you have the ability to then have some pharmacodynamic flexibility when you're going after this type of target. So if you're trying to antagonize downstream, you know, you might need to have 100% target occupancy, 24/7 target coverage. When you're doing this upstream agonism, there's an exaggerated PD effect, and you can hit the target, have the downstream effect without kind of constantly being on the target or occupying kind of all of the target. And we think that's important because every IPF patient is different, right?
Different levels of disease progression, different levels of receptor expression. As I'd mentioned, so not only do we think we have the right target, but we also have the right tissue, and kind of the schematic at the left reflects that, where we did labeled work with angiotensin II on healthy human lung tissue and confirmed that there's a high level of expression of this AT2 receptor that we're agonizing. Now, not only do we know that this target is highly expressed in human lung tissue, but we actually know through the work of Vicore and academic groups the precise cell type where it's largely expressed in the lung, and that's on these precursor cells called alveolar epithelial type II cells. So the question then becomes, what exactly do these AEC2 cells do for the healthy functioning of an alveolus? And there are two key functions that we'd highlight.
One is these AEC2 cells are the precursor cell that differentiate into the workhorse of the alveolus, the AEC1 cells, and these alveolar epithelial type I cells are the cells responsible for gas exchange. The second function that we'd really highlight is these AEC2 cells produce surfactant protein, and surfactant protein is quite important for the healthy functioning of an alveolus. So if you think of the alveolus as a water-containing compartment, the surface tension associated with water in the absence of surfactant would cause the alveolus to collapse, and so, the production of surfactant becomes quite important in this disease state. And actually what's known about IPF is that one of the features of early disease is prefibrotic alveolar collapse due to loss of surfactant production.
Now, then, you know, kind of the next question you can ask is, okay, those are two key functions of the AEC2 cells, the differentiating into gas exchange cells and production of surfactant to keep the alveolus animated. What happens in the IPF disease state? And so there are a few things that we'd highlight here. First and foremost, the micro-injury to the lung that exists in the disease state of IPF drives the death and dysfunction of these alveolar epithelial type II cells. So they're no longer differentiating and repopulating the AEC1 gas exchange cells, and they're no longer producing surfactant protein. So that's maybe the first step. The second piece of the puzzle is this damage also triggers the release of TGF-beta1, both from alveolar epithelial type II cells as well as from macrophages in the alveolus.
And that TGF-beta1 drives a number of profibrotic functions, including what's called the epithelial to mesenchymal transition. So actually what now happens because of TGF-beta1 is the AEC2 cells that would otherwise differentiate into gas exchange are pushed to differentiate into fibroblasts and ultimately myofibroblasts, and those are the very cell type that do the collagen deposition and drive the fibrotic process. In addition to that, epithelial to mesenchymal transition, and production of myofibroblasts, the drive in TGF-beta1 also leads to an imbalance in the matrix metalloproteinases, and in particular a downregulation of the collagenase type MMPs, the matrix metalloproteinases that would otherwise chop up the collagen matrix to resolve some of the fibrosis in the lung interstitium. So then the question becomes, okay, what happens when you agonize this AT2 receptor with your drug candidate, you know, C21?
There are a number of things that happen both in the endothelium and in the epithelium. Three things that we'd really highlight that we think drive some of our therapeutic efficacy are, first and foremost, a survival signal and a promotion of AEC2 cell viability. So agonizing this target on AEC2 cells allows them to continue to survive and also allows them to continue to differentiate into the alveolar epithelial type I cells as well as continuing to produce surfactant production, continuing to produce surfactant. The second piece that we'd highlight is that this mechanism inhibits TGF‑β1, and this is again what's nice about an upstream mechanism of action.
When I say it inhibits TGF‑β1, we have evidence that it inhibits the expression of TGF‑β1, TGF‑β receptor that it signals on, and also that it inhibits signaling through the two key pathways, in particular the Smad pathways that drive the fibrotic activity of the TGF‑β1 pathway. Then the third piece that we'd highlight is an inhibition of this epithelial to mesenchymal transition. As these AEC2 cells are pushed to differentiate into fibroblasts and then ultimately myofibroblasts, agonizing the AT2 receptor will block that process, and when you have a myofibroblast, they actually still express that AEC2, that AT2 receptor, and agonizing that target downregulates their collagen-producing activity.
Now we have a strong body of preclinical literature, and experiments around this that I'm happy to share, but, you know, we'll I just wanted to highlight kind of one or two pieces of this story. And so this is work with precision cut human lung slices. So this is for IPF patients who've progressed so far that they're eligible for lung transplant, you can obtain some of that human IPF lung tissue, and you can actually then add your drug and see the impact on different proteins, and ultimately collagen production as well. And so what we see here actually is that at clinically relevant concentrations, the activation of the AT2 receptor with our drug C21 is able to drive down TGF-β1 levels as we'd expect for this mechanism and is also able to reduce collagen protein levels, as well.
In addition to reducing the expression of TGF-β1 itself, in different experiments we've also shown the ability for C21 to inhibit the signaling of TGF-β1 through the Smad2/3 pathways, and that's what's shown here as well. But we don't just see this in our preclinical and translational studies. This is actually some data from our clinical IPF trials. So this is phase IIA study in patients with IPF where we measured TGF-β1 in plasma at baseline and after six months of treatment with our drug 100 mg pill twice daily. You can see here a number of patients at baseline have elevated levels of plasma TGF-β1.
The hypothesis here is that there's so much production in a subset of patients in our study of TGF‑β1 that it's spilling over into the periphery that we can measure it, and after six months of treatment with our drug we're able to show that we can bring it down. So a nice confirmation of that mechanism of action in terms of reducing TGF‑β1 expression. But maybe from here I'll move to talk a little bit more about then the phase IIA study. So we did an open-label phase IIA study in treatment-naïve IPF patients. We tested our drug in monotherapy. We had central reading on the high-resolution CT scans that were used as part of the diagnostic criteria as well as central overread on FVC measurements throughout the study.
And then we did an interim analysis on this study in May of 2023, and that's what I can share with you here today. So here we have on the right-hand column, on the safety and tolerability side, the treatment-emergent adverse events. And what you can see is that this is quite differentiated from, for example, the Nintedanib standard of care, where we don't have the GI side effect profile, or some of the other effects that are associated with the disease. Even things like cough, which are typically associated with disease, were reported at lower levels in our study. We also had no treatment-related serious adverse events for this study, and that's really nice in terms of showing the safety and tolerability of a potential therapy for IPF that's quite differentiated from standard of care.
Actually C21 has now been exposed to 366 individuals in different clinical studies and shown a very nice safety and tolerability profile. I think that's, you know, kind of not to be understated because, for such an upstream mechanism of action, to be able to be dosed in a safe and well-tolerated way based on our clinical data to date is quite, quite exciting from our perspective. Now in addition to the, you know, safety and tolerability, what's really nice then is what we're seeing initially on the efficacy side as well. So what you see here is the FVC change in the interim analysis that we conducted, and what you see here is for 12 to six weeks a stabilization of FVC, and then followed by a period of improvement in lung function as measured by FVC out to 36 weeks.
And that's quite different from what you might expect from the standard of care therapies, which are kind of shown below, as well as from the untreated patient population. Now on the right here you'll see some different segmentation of the FVC kind of subgroups. And one thing that I'd highlight is it's really nice to see that in patients with the entrenched fibrosis, the typical UIP patients, and then those are shown in the green dot above the baseline, those are patients that have evidence of honeycombing on their high-resolution CT scans. So basically so much fibrosis that it's broken down the normal tissue, typically in the lower lobes, and that tissue's probably gone. So those are really kind of established disease patients.
And to show that you can improve lung function even in that group for us, I think, is also quite exciting. Now you'll see at the top kind of who's driving the kind of outsized response, and that's the probable UIP patients. And that's also consistent with the mechanism of action if you think about, for example, the ability to drive production of surfactant protein impacting FVC positively in kind of patients who have lower levels of fibrosis or even prefibrotic state as well. So, so we think that's quite, quite exciting, quite nice to see, and also quite consistent with the mechanism of action.
I would also say that while agonizing this AT2 receptor with our drug has some anti-inflammatory properties, that's not the dominant effect of our drug, and that's one of the reasons why, you know, we don't have so quick improvement in FVC, this kind of bronchodilator type effect that you might see with other therapies, but rather resolving the fibrosis, reducing the extracellular matrix by increasing the level of matrix metalloproteinases, replenishing the alveolar epithelial type I cells is the type of thing that we think takes, you know, weeks and months, and that's reflected in this data set as well. We also were able to do a little bit of work on baseline high-resolution CT scans in our study, and here that's reflected, in kind of the left-hand side, kind of an analysis of the fibrosis pattern of our high-resolution CT scans confirming that these are IPF patients.
Also, a nice correlation between the baseline high-resolution CT scans and baseline FVC, which is quite good to see and kind of confirms the quality associated with the FVC measurements as well as kind of the diagnostics in the study as well. So moving maybe from the phase IIA data, we were really excited to report last month a partnership with Nippon Shinyaku for C21 in Japan. So we've outlicensed the Japanese rights to the drug to them. They're a real expert in the development of rare respiratory disease drugs. They are responsible for the discovery and development of Uptravi, blockbuster PAH drug, as well as several other PAH drugs. And so we think they're the great partner for our program in Japan.
They know the physicians, they know the commercial landscape, and the financial terms were also nice: $10 million upfront, $275 million in milestones, as well as royalties into the low, into the low 20s%. Now for, for Vicore, after we report the phase IIA data in the first half of this year, we'll actually at the same time seek to initiate a phase IIB study, and we're really looking for this phase IIB study to be, you know, as much as possible, as much as possible the definitive answer on the efficacy of this molecule and de-risking for phase III development. So it's designed as a randomized, placebo-controlled global study. It'll be including patients who are on Nintedanib standard of care as well as those not on standard of care.
There'll be a 52-week treatment duration, where we're measuring change from FVC at baseline, so the same as a phase III endpoint. We'll enroll 270 patients, 90 per arm, and the objective here is with a successful phase IIB readout that we would seek to request from FDA that we would have to run only one phase III study, whereas typically, prior IPF therapies run two phase III. So really looking for kind of a robust study here that provides us with, you know, a clear picture on the safety and the efficacy of this of this molecule. The final point that I'd maybe make here is that the 270 patients that we're seeking to enroll in the study are designed to power the study to detect stabilization of lung function out to 52 weeks.
So basically, you know, it's very interesting to see this improvement of lung function in our phase IIA study, and we actually think that's quite exciting, and we're looking forward to hopefully seeing that again. But at the same time, you know, there's such a high unmet need in this space, and certainly it would be quite exciting for patients to have a therapy that even stabilizes their lung function. So we wanted to make sure to power our phase IIB accordingly. So I'm happy to stop there and take any questions.
So your first time said that those were all, that was all in India?
It wasn't all in India. It was 70% out of India.
Okay. So we think we did a broader study in different geographies. Would that lead to different results if they've done any work on it on that?
Yeah. We've looked at that. We don't think so. We also had central reading of the spirometry, so one physician, one radiologist out of the U.K. looked at every single patient's high-resolution CT scan to confirm that they had IPF centrally, and so the patients that were enrolled would have both diagnostics as well as imaging consistent with IPF, you know, outside of India as well.
In the phase IIB, what countries have that technically?
We'll be going for 14 countries. One of the primary reasons why we went for India in the phase IIA was the availability of treatment-naïve patients. Because we are not, we're allowing standard of care in the phase IIB, we will not be needing to include India. So it'll be heavy in the United States, South Korea, Taiwan, Argentina, Canada, Mexico, U.K., other Western European countries.
What kind of IP do you have?
Yeah. So the drug is protected by broad formulation and method of use IP that's issued in the United States and Europe that extends out to 2045, 2046 if you include patent term extension and SPC. In addition, there's regulatory exclusivities around the drug, so it would be seven years of orphan exclusivity in the U.S., 10 years in Europe. Composition of matter would expire prior to anticipated launch.
Would phase IIB exclude patients at such a time?
That's a good question. I'm not sure. I mean, yeah.
Because you understand what I'm asking, to the extent that the drug mechanism is expression of TGF-beta1, are you going to shut it down on something?
Inhibition. I would guess that we don't necessarily include patients who are on Sotatercept. I have to get back to you on that one. I would also imagine that, yeah, patients aren't on Sotatercept. I would also have to look at what the overlap is between PAH and IPF. Obviously there's a big overlap PH-ILD, IPF, but I'm not sure about the PAH-IPF overlap. Yeah.
Where is the two receptors located? Are they in one alveolar cells?
So they're predominantly on alveolar epithelial type II cells. They also exist on the cells that ultimately differentiate from them. So there's some expression on alveolar epithelial type I, and there's some expression on the fibroblast and the myofibroblast as well. There's also expression on some cells in the endothelium as well.
Can you make a knockout model?
So there have been animal knockout models produced. In an animal knockout of the AT2 receptor, there was an interesting preclinical paper, I think in Nature a few years ago, where they knocked out the AT2 receptor and then damaged the lung through some chemical injury, and showed that the AT2 receptor knockout did not repair the tissue as quickly as a wild-type mouse. So kind of showing that this mechanism is probably driven when you do have a response to injury in order to do some repair. No, not that I'm aware of, yeah. The mice were healthy that had the knockout.
What's the ligand? Is it regular angiotensin that hits the AT2R?
Yes. So it's the peptide angiotensin II that hits the AT2R, as well as some of these fragments that are listed here, so the angiotensin 1-9 fragment as well as the 1-7.
Do IPF patients who have hypertension or coronary heart disease have the worst outcome?
What's interesting is there's a little bit of literature. A small clinical study was conducted with an AT1R antagonist, Losartan, and there's evidence that there might be some therapeutic benefit to blocking the AT1 receptor. That wouldn't be shocking in the sense that, right, we talk about the AT1 receptor as being also, in addition to driving hypertension, some inflammation as well as fibrosis. I think that if you're on Losartan or some other angiotensin receptor blocker, that could actually be beneficial.
ACE inhibitor?
An ACE inhibitor shouldn't. I mean, yeah, it's a good—it's a good question. I, to be honest with you, I don't know the answer to that, right? It does deplete the population of angiotensin II. I, I, I'm not aware if there's any literature on that, on that aspect. I haven't seen anything like that.
Last one, Your Honor.
Yeah?
If I heard you correctly, that it was unusual, you have the TGF-beta in blood. I thought I heard you say that the hypothesis is you've got so much local TGF-beta production in the lungs, but it's still observable in the periphery.
Yeah. Yes.
What you showed, you showed a drop in TGF-beta in the periphery, effectively detecting anyone in the periphery. Suggests that your interstitial in the lungs is still saturated despite use of drug. So even if you're cutting your systemic identification of TGF-beta by 60%, 90%, you've got enough in the interstitial that you're spilling over, but you're saturating the interstitial.
I think what we show here, do you mean the detection levels at week 24 that there's still some nanogram?
If there's any, if you're telling me that the baseline should be none and you're still detecting some, that's why it matters.
So it's a good question. I think that the measurement of—I mean, it'll be very interesting to look at what this picture looks like over time and in a bigger patient population. I think that the reason why you have to take some of this with a bit of a grain is, you know, there is, of course, always a waxing and waning in TGF-beta1 expression, and what's most important is the local—ultimately the local levels. But we certainly see it as supportive that we're driving the mechanism of action. And I certainly think that the mechanism is not an absolute on kind of, right, just inhibiting the expression of TGF-beta1, for example. It also inhibits the signaling of the pathway. So I don't think it's necessarily relying on having to kind of be 100% block on TGF-beta1.
Of course, what's also nice to see is this drug has a really nice safety and tolerability profile to date, whereas we know systemic blockade of TGF-beta1, for example, can have some side effects as well.
What did you land on for clinical work?
Yeah. So we did some dose modeling work, and we basically used our entire picture of preclinical and translational evidence to make an estimate for what concentrations we felt we needed to achieve in the lung tissue in order to have a therapeutic benefit. We basically, you know, based on the phase I and PK data, calculated from there what dose we felt we needed to take in order to ultimately have the suitable concentrations in the lung.
What kind of saturation was what you're getting over time in the process?
So we think that at the 100 milligram twice-daily dose, we're getting above IC90 levels of activity in the lung. So we think that this is a CMAX-driven effect. So we think we're hitting, you know, when you kind of take your twice-daily dose, that you're hitting it twice, on the CMAX kind of effect. We don't think it's AUC-driven, and we don't think necessarily you need kind of full, full target occupancy or kind of full, full, target coverage 24/7.
What's the moment suggested for the effective dose?
above IC50. So we think that the 50 mg dose may also be effective.
But a much lower effective than a target effect if you're entering an IC50 dose estimate?
That's right. I mean, we'll have to see how, right, that in vitro data then translates to a clinical benefit, right? So there are a lot of assumptions you have to make in the kind of between what you see in an in vitro model and then ultimately what drives the clinical benefit. As I kind of mentioned, we think that there's quite an exaggerated PD effect for this mechanism of action. So you hit the target and actually has the ultimate downstream effects. So if you're taking this twice daily over quite an extended period of time, we think you could ultimately still have, you know, similar therapeutic benefit, but we'll have to see that in our phase IIB.
What's in metabolites?
in terms of.
Hepatic excretion or excretion?
Oh, I think it's.
Metabolites and therapy?
Yeah. So I think it's a hepatic excretion, and I think there are a few main metabolites that we've identified. It's a pretty quick process.
Does anyone else have an angiotensin receptor like you guys that you're aware of?
No. As far as we're aware, no one's currently working on agonizing this pathway. There have been some prior efforts, early stage, but nothing that's advanced.
And the reason why we're here is, I don't know if you know if you've talked to someone else, but he said the Cleveland Clinic. But he said, like, "I am most excited about this mechanism." I think that's the, the right quote. And this data is very, very real, and everyone's just saying, "Okay." So, that's pretty encouraging.
Yeah. Yeah. No, it's great to have the support from the clinical community at the Cleveland Clinic and, yeah, and other institutions. So we're fortunate to have, you know, kind of folks, I think, who are excited about this mechanism, one that it's safe and well-tolerated, also that it's showing such promising effects, and also just mechanistically that it's quite different from some of the other approaches as well.
Great.
Wonderful. Well, thank you all for the time.